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Biomedical subjects

M Hughes

Publications and source records attributed to M Hughes.

At least 109 records · Page 6Linked to original sources
PubMed1997

Xenopus Ran-binding protein 1: molecular interactions and effects on nuclear assembly in Xenopus egg extracts.

Ran is a nuclear GTPase implicated in nucleocytoplasmic transport, the maintenance of nuclear structure, mRNA processing, and cell cycle regulation. By two-hybrid interaction in yeast, we have identified a Xenopus homologue of Ran-binding protein 1 (RanBP1). Xenopus RanBP1 interacts specifically with the GTP-bound form of Ran and forms complexes in Xenopus egg extracts with Ran, importin-beta/karyopherin-beta and importin-alpha/karyopherin-alpha, but not p10, p120/RanBP7, RanBP2 or other nucleoporins. These complexes may play roles in the recycling of Ran and importins/karyopherins during nucleocytoplasmic transport. Increased concentrations of RanBP1 stabilise an interaction between Ran and RCC1 in egg extracts, inhibiting the exchange activity of RCC1 towards Ran. Under these conditions, the assembly of nuclei from chromatin is dramatically affected: the nuclei do not assemble a lamina and become very small with homogeneously condensed chromatin. They fail to actively import proteins and do not undergo DNA replication. By field emission in-lens scanning electron microscopy, we show that these nuclei have an intact nuclear envelope containing pore complexes, but the envelope is highly convoluted. However, RanBP1 does not directly inhibit nuclear protein import in assembled nuclei. These results suggest that RCC1 and/or Ran have a function early in nuclear assembly that is disrupted by RanBP1.

Amino Acid Sequence↗
PubMed1997

Does pancreatic enzyme supplementation reduce pain in patients with chronic pancreatitis: a meta-analysis.

OBJECTIVE: Pancreatic enzyme therapy is widely used in the treatment of pain in chronic pancreatitis. The aim of our study was to perform a meta-analysis to determine whether pancreatic enzyme supplementation significantly decreases abdominal pain in patients with chronic pancreatitis. METHODS: From a MEDLINE search, we identified, evaluated, and subjected to a meta-analysis, six randomized, double-blind, placebo-controlled trials. Important features of data extraction included the method of subject inclusion, definition of disease, enzyme preparation, response to pancreatic enzyme therapy versus placebo, and modality for measuring response. RESULTS: In the meta-analysis, the pooled estimate of the percentage of patients per study who preferred enzymes relative to placebo was 52% (95% confidence interval, 45-60%). A test of homogeneity indicated that there was no statistically significant heterogeneity across studies in the percentage of patients preferring enzymes. CONCLUSION: Statistical analysis demonstrates no significant benefit of supplemental pancreatic enzyme therapy to relieve pain associated with chronic pancreatitis.

Chronic Disease↗
PubMed1996

A temperature-sensitive splicing mutation in the bimG gene of Aspergillus produces an N-terminal fragment which interferes with type 1 protein phosphatase function.

Progression through anaphase requires high levels of type 1 protein phosphatase (PP1) activity in a variety of eukaryotes, including Aspergillus nidulans. A conditional lethal, temperature-sensitive mutant in one of the Aspergillus PP1 genes, bimG, prevents the normal completion of anaphase when cells are grown at restrictive temperature and this has been shown to be due to a reduction in type 1 phosphatase activity. We show that the bimG11 allele is recessive to the wild-type allele in heterozygous diploids, implying that the mutation is due to loss of function at restrictive temperature, but molecular disruption of the wild-type bimG gene shows that the gene is not essential and has no discernable phenotype under laboratory conditions. Sequence comparison of wild-type and mutant alleles reveals a single base pair difference between the two genes, within the 5' splicing site of the second intron. We demonstrate that the conditional lethal phenotype of bimG11 strains is due to impaired splicing of the mutant mRNA and that this leads to the production of a truncated protein comprising an intact N-subdomain and a modified C-terminus. Over-expression of this truncated form of PP1 in a wild-type haploid produces a lethal phenotype and reduced PP1 activity, supporting the idea that a toxic interfering protein is produced. PP1, therefore, may have at least two spatially separated sites, both of which are required for function. Temperature-sensitive splicing mutations may provide a novel means of engineering conditional versions of other proteins, particularly other phosphatases.

Alleles↗
PubMed1996

Zidovudine side effects as reported by black, Hispanic, and white/non-Hispanic patients with early HIV disease: combined analysis of two multicenter placebo-controlled trials.

The objective of this study was to determine whether HIV patients' subjective tolerance of zidovudine differs by racial or ethnic grouping by conducting a post hoc analysis of reported symptoms in two multicenter, placebo-controlled trials of zidovudine monotherapy for early HIV disease. Ratios of rates of developing new or worsening symptoms as reported by patients assigned to active drug or placebo were compared in groups of white/non-Hispanic, black, or Hispanic origin. Patients were included in the study if they had asymptomatic HIV disease and entry absolute CD4 lymphocyte counts below 500 cells/microL and were enrolled in National Institute of Allergy and Infectious Diseases AIDS Clinical Trials Group (ACTG) protocol 019 or had mild symptoms of HIV disease, were enrolled in ACTG protocol 016, met protocol eligibility criteria for the respective trial, and were categorized at entry as white/non-Hispanic (N = 1801), black (N = 195), or Hispanic (n = 214). The primary outcome measure was development of a new or worsening symptom of any severity. Among patients treated with zidovudine compared with placebo, the estimated risk for developing a new or worsening symptom was not significantly greater for blacks or Hispanics than for white/non-Hispanics for any of the most frequently reported symptoms (p > 0.05 after adjustment for the multiple comparisons performed). Our analysis of 195 black and 214 Hispanic patients did not reveal a significantly increased risk of subjective zidovudine intolerance compared with white/non-Hispanic subjects. If there is an increased risk of such intolerance in minority groups compared with white/non-Hispanics, it is not likely to be clinically important.

Acquired Immunodeficiency Syndrome↗
PubMed1996

Clinical experience with preimplantation genetic diagnosis of cystic fibrosis (delta F508).

Preimplantation genetic diagnosis (PGD) was attempted in 12 couples in whom both parents carry the common delta F508 deletion causing cystic fibrosis (CF). In vitro fertilization (IVF) was followed by cleavage stage biopsy on days 2 and 3 and removal of one or two cells for genetic analysis by nested polymerase chain reaction (PCR) and heteroduplex formation. A total of 18 cycles resulted in 137 normally fertilized embryos, of which 115 developed to cleavage stages and 114 were successfully biopsied. Genetic analysis was successful in 83 embryos (73 per cent). With the remaining embryos, either results from two or more cells were discordant or amplification failed. In 15 cycles, one or two either normal or carrier embryos were transferred and five (33 per cent) clinical pregnancies were established. Five singletons have been born and at birth all five babies have been confirmed as homozygous for the normal allele. Our experience demonstrates that IVF and cleavage stage biopsy consistently provides sufficient embryos, diagnosed as unaffected, for transfer in this autosomal recessive disease and that pregnancy rates are comparable to those following IVF.

Adult↗
PubMed1996

Urinary trypsinogen activation peptides (TAP) are not increased in mild ERCP-induced pancreatitis.

Acute pancreatitis following endoscopic retrograde cholangiopancreatography (ERCP) occurs in 3-18% of patients undergoing either diagnostic or therapeutic ERCP. We prospectively measured urinary trypsinogen activation peptides (TAP) by an automated anti-TAP enzyme-linked immunoassay among 107 patients 4 h after ERCP to determine whether this measurement helps in the early diagnosis of ERCP-induced pancreatitis. Pancreatitis was documented in 10 of 107 patients (9.3%). All episodes were graded as mild. Urinary TAP was not significantly increased. We conclude that measurement of urinary TAP 4 h after ERCP is not helpful in documenting mild ERCP-induced acute pancreatitis.

Acute Disease↗
PubMed1996

Cutaneous lesions in a case of acute megakaryoblastic leukaemia.

We describe the case of a 68-year-old woman who presented with asymptomatic skin nodules and symptoms of anaemia, and was found to have acute megakaryoblastic leukaemia with fibrosis, a condition now believed to correspond to the former diagnosis of acute myelofibrosis. There is only one previous report of skin lesions developing in this condition.

Aged↗
PubMed1996

Mammographically negative breast cancer at the Strathfield Breast Centre.

BACKGROUND: The current diagnostic modalities used to detect breast cancer are mammography, together with clinical examination, ultrasound and fine needle aspiration biopsy (FNAB). The accuracy rates for each modality varies and a combination of the modalities is recommended to detect cancer early. Some authors have suggested that mammography should be used primarily as a screening tool because of the false negative mammography results that have been reported in the past 10 years. The records of patients at the Strathfield Breast Centre were reviewed to determine the accuracy of other modalities. METHODS: The records of 371 breast cancer patients treated at the Strathfield Breast Centre in the 6 years form 1989 to 1994 were reviewed to determine the accuracy of mammography, ultrasound, clinical examination and fine needle aspiration biopsy. Of the 371 women with histopathologically diagnosed breast cancer, 349 had mammography. RESULTS: The accuracy rate of mammography in the present study was 91% with a false negative rate of 9%. It was found that there was no significant delay in treatment of breast cancer in mammogram-negative patients. CONCLUSIONS: Mammographically negative breast cancer was found to be more common in younger women, to be similar in size to mammogram-positive cancer, to occur in all histological types and grades and was usually invasive rather than noninvasive. The rate of lymph node involvement was similar to the mammogram-positive group.

Adult↗
PubMed1996

Immunogenicity and efficacy against lethal aerosol staphylococcal enterotoxin B challenge in monkeys by intramuscular and respiratory delivery of proteosome-toxoid vaccines.

Staphylococcal enterotoxin B (SEB), a primary cause of food poisoning, is also a superantigen that can cause toxic shock after traumatic or surgical staphylococcal wound [correction of would] infections or viral influenza-associated staphylococcal superinfections or when aerosolized for use as a potential biologic warfare threat agent. Intranasal or intramuscular (i.m.) immunization with formalinized SEB toxoid formulated with meningococcal outer membrane protein proteosomes has previously been shown to be immunogenic and protective against lethal respiratory or parenteral SEB challenge in murine models of SEB intoxication. Here, it is demonstrated that immunization of nonhuman primates with the proteosome-SEB toxoid vaccine is safe, immunogenic, and protective against lethal aerosol challenge with 15 50% lethal doses of SEB. Monkeys (10 per group) were primed i.m. and given booster injections by either the i.m. or intratracheal route without adverse side effects. Anamnestic anti-SEB serum immunoglobulin G (IgG) responses were elicited in all monkeys, but strong IgA responses in sera and bronchial secretions were elicited both pre- and post-SEB challenge only in monkeys given booster injections intratracheally. The proteosome-SEB toxoid vaccine was efficacious by both routes in protecting 100% of monkeys against severe symptomatology and death from aerosolized-SEB intoxication. These data confirm the safety, immunogenicity, and efficacy in monkeys of parenteral and respiratory vaccination with the proteosome-SEB toxoid, thereby supporting clinical trials of this vaccine in humans. The safety and enhancement of both bronchial and systemic IgA and IgG responses by the proteosome vaccine delivered by a respiratory route are also encouraging for the development of mucosally delivered proteosome vaccines to protect against SEB and other toxic or infectious respiratory pathogens.

Aerosols↗
PubMed1996

A comparison of maximal bioenergetic enzyme activities obtained with commonly used homogenization techniques.

Homogenization of tissue for analysis of bioenergetic enzyme activities is a common practice in studies examining metabolic properties of skeletal muscle adaptation to disease, aging, inactivity or exercise. While numerous homogenization techniques are in use today, limited information exists concerning the efficacy of specific homogenization protocols. Therefore, the purpose of this study was to compare the efficacy of four commonly used approaches to homogenizing skeletal muscle for analysis of bioenergetic enzyme activity. The maximal enzyme activity (Vmax) of citrate synthase (CS) and lactate dehydrogenase (LDH) were measured from homogenous muscle samples (N = 48 per homogenization technique) and used as indicators to determine which protocol had the highest efficacy. The homogenization techniques were: (1) glass-on-glass pestle; (2) a combination of a mechanical blender and a teflon pestle (Potter-Elvehjem); (3) a combination of the mechanical blender and a biological detergent; and (4) the combined use of a mechanical blender and a sonicator. The glass-on-glass pestle homogenization protocol produced significantly higher (P < 0.05) enzyme activities compared to all other protocols for both enzymes. Of the four protocols examined, the data demonstrate that the glass-on-glass pestle homogenization protocol is the technique of choice for studying bioenergetic enzyme activity in skeletal muscle.

Adaptation, Physiological↗
PubMed1995

GTBP, a 160-kilodalton protein essential for mismatch-binding activity in human cells.

DNA mismatch recognition and binding in human cells has been thought to be mediated by the hMSH2 protein. Here it is shown that the mismatch-binding factor consists of two distinct proteins, the 100-kilodalton hMSH2 and a 160-kilodalton polypeptide, GTBP (for G/T binding protein). Sequence analysis identified GTBP as a new member of the MutS homolog family. Both proteins are required for mismatch-specific binding, a result consistent with the finding that tumor-derived cell lines devoid of either protein are also devoid of mismatch-binding activity.

Amino Acid Sequence↗
PubMed1995

A new antigen receptor gene family that undergoes rearrangement and extensive somatic diversification in sharks.

Immunoglobulin and T-cell receptor (TCR) molecules are central to the adaptive immune system. Sequence conservation, similarities in domain structure, and usage of similar recombination signal sequences and recombination machinery indicate that there was probably a time during evolution when an ancestral receptor diverged to the modern-day immunoglobulin and TCR. Other molecules that undergo rearrangement have not been described in vertebrates, nor have intermediates been identified that have features of both these gene families. We report here the isolation of a new member of the immunoglobulin superfamily from the nurse shark, Ginglymostoma cirratum, which contains one variable and five constant domains and is found as a dimer in serum.

Amino Acid Sequence↗
PubMed1995

Prevalence and correlates of drug use and dependence in the United States. Results from the National Comorbidity Survey.

OBJECTIVES: To analyze nationally representative data on the lifetime and 12-month prevalences of use of and dependence on illegal drugs (marijuana/hashish, cocaine/crack, heroin, hallucinogens), nonmedical prescription psychotropic drugs (sedatives, tranquilizers, stimulants, analgesics), and inhalants; and to examine data on the sociodemographic correlates of use and dependence. METHODS: The data come from the National Comorbidity Survey, a structured diagnostic interview administered to persons aged 15 to 54 years that generates reliable diagnoses according to the definitions and criteria of DSM-III-R. RESULTS: Of the respondents, 51.0% used one of the above drugs at some time in their lives, and 15.4% did so in the past 12 months. These estimates are similar to those obtained in the 1991 National Household Survey of Drug Abuse, where lifetime prevalence was 45.2% and 12-month prevalence was 16.7% among respondents in the age range 15 to 54 years. Of National Comorbidity Survey respondents, 7.5% (14.7% of lifetime users) were dependent at some time in their lives and 1.8% were dependent in the past 12 months. The prevalence estimate for lifetime dependence was reduced to 5.3% when calculated the percentage of respondents in the age range of 28 to 54 years who reported an onset of dependence as of 10 years earlier (ie, when they were 18 to 44 years old) was computed. This is similar to the Epidemiologic Catchment Area Study estimate of 5.1% among respondents in the age range 18 to 44 years, a comparison that matches the two studies on year of assessment, age of risk, and cohort. Males were significantly more likely to report both lifetime and 12-month use and dependence. Use and dependence were found to be more common in cohorts born after World War II than those born before the end of the war. The demographic predictors of lifetime use differed from the predictors of lifetime dependence among users, and these, in turn, differed from the predictors of recent dependence among people with a lifetime history of dependence. CONCLUSIONS: Drug use and dependence are highly prevalent in the general population. The fact that there are differences in the correlates of first use, dependence among users, and persistence of dependence means that future research aimed at pinpointing modifiable risk factors must be based on disaggregated analyses of separate stages of progression.

Adolescent↗
PubMed1995

Posttraumatic stress disorder in the National Comorbidity Survey.

BACKGROUND: Data were obtained on the general population epidemiology of DSM-III-R posttraumatic stress disorder (PTSD), including information on estimated life-time prevalence, the kinds of traumas most often associated with PTSD, sociodemographic correlates, the comorbidity of PTSD with other lifetime psychiatric disorders, and the duration of an index episode. METHODS: Modified versions of the DSM-III-R PTSD module from the Diagnostic Interview Schedule and of the Composite International Diagnostic Interview were administered to a representative national sample of 5877 persons aged 15 to 54 years in the part II subsample of the National Comorbidity Survey. RESULTS: The estimated lifetime prevalence of PTSD is 7.8%. Prevalence is elevated among women and the previously married. The traumas most commonly associated with PTSD are combat exposure and witnessing among men and rape and sexual molestation among women. Posttraumatic stress disorder is strongly comorbid with other lifetime DSM-III-R disorders. Survival analysis shows that more than one third of people with an index episode of PTSD fail to recover even after many years. CONCLUSIONS: Posttraumatic stress disorder is more prevalent than previously believed, and is often persistent. Progress in estimating age-at-onset distributions, cohort effects, and the conditional probabilities of PTSD from different types of trauma will require future epidemiologic studies to assess PTSD for all lifetime traumas rather than for only a small number of retrospectively reported "most serious" traumas.

Adolescent↗
PubMed1995

Observed sleep/wakefulness and severity of dementia in an Alzheimer's disease special care unit.

BACKGROUND: This study tested the hypothesis that behaviorally defined sleep disturbance among residents in a Special Care Unit (SCU) for Alzheimer's disease (AD) was related to the severity of their dementia. Previously, sleep laboratory studies have reported such relationships when sleep has been recorded polysomnographically over several nights. Observational studies of sleep have not shown such relationships, presumably because of the impression involved in determining sleep/wake state behaviorally. METHODS: Nightly sleep data based on observations made every two hours by nursing staff for a period of 13 to 18 months were examined for 47 AD residents with a mean age of 80.7 +/- 6.5 years. Level of dementia and functional capacity were assessed with the Mattis Dementia Rating Scale (DRS) and the Katz Activities of Daily Living Scale (ADL). RESULTS: Data indicated that these SCU residents experienced a moderately disturbed night of sleep an average of 24% +/- 10% of their nights in the facility and a severely disturbed night of sleep on 7% +/- 6% of those nights. More profound dementia was associated with more sleep disturbance; however, incapacity in ADLs, age, gender, and psychoactive medications were unrelated to such disturbances. CONCLUSIONS: The results indicate that patterns of relationships noted between laboratory-based measures of sleep and variables such as severity of dementia can be detected using behavioral observations of sleep, provided that the number of nights of observation are sufficiently large to offset the measurement error involved in their use.

Aged↗
PubMed1995

Disruptive nocturnal behavior in Parkinson's disease and Alzheimer's disease.

Disruptive nocturnal behavior, often referred to as sundowning, is a commonly encountered clinical problem in most forms of dementia. This study compared disruptive nocturnal behavior in patients with Alzheimer's disease (AD) and Parkinson's disease (PD). Questionnaire data were collected from 60 AD and 48 PD caregivers. Respondents were asked to record the typical time of day when any of seven disruptive behaviors were evidenced in their patients, if at all. Two scores were computed: (1) a sundowning score (number of nocturnal disruptive behaviors, range 0-7), and (2) a total score (number of disruptive behaviors without regard to time, range 0-7). Results indicated PD patients were more likely than AD patients to exhibit disruptive nocturnal behavior. The dose, timing, or number of years on antiparkinsonian medication were not related to nocturnal disruptive behavior within the PD patient group. These findings raise the possibility that sundowning in PD patients may be a manifestation of dopaminergic depletion within the basal ganglia or other abnormalities involving the cholinergic, serotoninergic and/or noradrenergic systems in the brainstem.

Aged↗